Obesity is a heritable disease that affects millions of people, is disproportionately prevalent in the Pima Indians of Southwestern Arizona, and has serious health consequences. The main scientific goals of the Obesity & Diabetes Clinical Research Section (ODCR) are to study (1) mechanisms of weight gain in Pimas and other human populations and (2) the pathophysiology of type 2 diabetes mellitus (T2DM) in non-obese and obese individuals. - Mechanisms of weight gain in Pimas and other human populations. It is generally thought that to treat the hyperphagia that leads to weight gain in the majority of people it will be crucial to understand the interaction between hedonic mechanisms regulating eating and the unconscious regulation of energy homeostasis in the hypothalamus. Using the Drewnowski taste test, a test used to assess preferences for sweet and creamy solutions, we observed that among adult Pima Indians, individuals who displayed a high hedonic response to these solutions were at high risk of developing obesity. This is likely because individuals with a high hedonic response to sweet and creamy solutions tend to eat in excess of their daily requirements, consume food with a high fat content and report eating in response to external rather than internal clues. Using positron emission tomography, a non invasive radiological technique that allows us to study patterns of brain activity associated with consumption of food, we observed that the pleasant taste of a forthcoming meal produced greater activation of the insular cortex in obese than in lean individuals, raising the possibility that this area of the brain may play a crucial role in the hedonic regulation of eating in humans - Pathophysiology of T2DM in non-obese and obese individuals. The adipose tissue is now recognized as an organ that secretes a large number of proteins, which are collectively referred to as adipokines. Our lab has continued to uncover evidence that an adipokine-induced activation of the immune system may mediate the effect of over nutrition on insulin resistance and later development of T2DM. In particular, we now have evidence that an increased adipocyte production of macrophage migration inhibiting factor (MIF), a cytokine with chemo attractant and proinflammatory properties, may be an important link between obesity and insulin resistance in adult Pimas. In contrast, we have excluded resistin, a novel adipokine with putative prodiabetogenic effects, as a major mediator of obesity-induced insulin resistance in this population. We are in the second year of a randomized, placebo controlled clinical trial designed to test if a short treatment with anti-inflammatory drugs improves insulin resistance in non-diabetic obese individuals with high markers of inflammation.